Azaindolizines and methods of use

Abstract

The invention relates to azaindolizines of formula I-a or I-b with anti-cancer and/or anti-inflammatory activity and more specifically to azaindolizines which inhibit MEK kinase activity. The invention provides compositions and methods useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder, or treating an inflammatory disease in a mammal. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

We claim: 
     
       1. A compound selected from Formula I-a or I-b: 
       
         
           
           
               
               
           
         
         and salts thereof, wherein: 
         Z A  is CR A ; 
         R A  is H, CF 3 , halo, C 1 -C 6  alkyl, or CN; 
         each of R 1 , R 2  and R 3  is independently H, C 1 -C 6  alkyl, halo, CN, CF 3 , —(CR 19 R 20 ) n NR 16 R 17 , —OR 16 , —SR 16  or —C(═O)NR 16 R 17 ; 
         W is 
       
       
         
           
           
               
               
           
         
         R 4  and R 5  are independently H or C 1 -C 12  alkyl; 
         X 1  is selected from R 7  and —OR 7 ; when X 1  is R 7 , X 1  is optionally taken together with R 5  and the nitrogen atom to which they are bound to form a 4-7 membered saturated or unsaturated ring having 0-2 additional heteroatoms selected from O, S and N, wherein said ring is optionally substituted with one or more groups selected from halo, CN, CF 3 , —OCF 3 , —NO 2 , oxo, —(CR 19 R 20 ) n C(═Y′)R 16 , —(CR 19 R 20 ) n C(═Y′)OR 16 , —(CR 19 R 20 ) n C(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n NR 16 R 17 , —(CR 19 R 20 ) n OR 16 , —(CR 19 R 20 ) n SR 16 , —(CR 19 R 20 ) n NR 16 C(═Y′)R 17 , —(CR 19 R 20 ) n NR 16 C(═Y′)OR 17 , —(CR 19 R 20 ) n NR 18 C(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n NR 17 SO 2 R 16 , —(CR 19 R 20 ) n OC(═Y′)R 16 , —(CR 19 R 20 ) n OC(═Y′)OR 16 , —(CR 19 R 20 ) n OC(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n OS(O) 2 (OR 16 ), —(CR 19 R 20 ) n OP(═Y′)(OR 16 )(OR 17 ), —(CR 19 R 20 ) n OP(OR 16 )(OR 17 ), —(CR 19 R 20 ) n S(O)R 16 , —(CR 19 R 20 ) n S(O) 2 R 16 , —(CR 19 R 20 ) n S(O) 2 NR 16 R 17 , —(CR 19 R 20 ) n S(O)(OR 16 ), —(CR 19 R 20 ) n S(O) 2 (OR 16 ), —(CR 19 R 20 ) n SC(═Y′)R 16 , —(CR 19 R 20 ) n SC(═Y′)OR 16 , —(CR 19 R 20 ) n SC(═Y′)NR 16 R 17 , and R 16 ; 
         each R 7  is independently H, C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; 
         X 4  is 
       
       
         
           
           
               
               
           
         
         R 6  is H, halo, C 1 -C 6  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, carbocyclyl, heteroaryl, heterocyclyl, —OCF 3 , —NO 2 , —Si(C 1 -C 6  alkyl), —(CR 19 R 20 ) n NR 16 R 17 , —(CR 19 R 20 ) n OR 16 , or —(CR 19 R 20 ) n —SR 16 ; 
         R 6′  is H, halo, C 1 -C 6  alkyl, carbocyclyl, CF 3 , —OCF 3 , —NO 2 , —Si(C 1 -C 6  alkyl), —(CR 19 R 20 ) n NR 16 R 17 , —(CR 19 R 20 ) n OR 16 , —(CR 19 R 20 ) n —SR 16 , C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, heterocyclyl, aryl, or heteroaryl; 
         p is 0, 1, 2 or 3; 
         each n is independently 0, 1, 2 or 3; 
         wherein each said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6′ , R 7 , and R A  is independently optionally substituted with one or more groups independently selected from halo, CN, CF 3 , —OCF 3 , —NO 2 , oxo, —Si(C 1 -C 6  alkyl), —(CR 19 R 20 ) n C(═Y′)R 16 , —(CR 19 R 20 ) n C(═Y′)OR 16 , —(CR 19 R 20 ) n C(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n NR 16 R 17 , —(CR 19 R 20 ) n OR 16 , —(CR 19 R 20 ) n SR 16 , —(CR 19 R 20 ) n NR 16 C(═Y′)R 17 , —(CR 19 R 20 ) n NR 16 C(═Y′)OR 17 , —(CR 19 R 20 ) n NR 18 C(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n NR 17 SO 2 R 16 , —(CR 19 R 20 ) n OC(═Y′)R 16 , —(CR 19 R 20 ) n OC(═Y′)OR 16 , —(CR 19 R 20 ) n OC(═Y′)NR 16 R 17 , —(CR 19 R 20 ) n OS(O) 2 (OR 16 ), —(CR 19 R 20 ) n OP(═Y′)(OR 16 )(OR 17 ), —(CR 19 R 20 ) n OP(OR 16 )(OR 17 ), —(CR 19 R 20 ) n S(O)R 16 , —(CR 19 R 20 ) n S(O) 2 R 16 , —(CR 19 R 20 ) n S(O) 2 NR 16 R 17 , —(CR 19 R 20 ) n S(O)(OR 16 ), —(CR 19 R 20 ) n S(O) 2 (OR 16 ), —(CR 19 R 20 ) n SC(═Y′)R 16 , —(CR 19 R 20 ) n SC(═Y′)OR 16 , —(CR 19 R 20 ) n SC(═Y′)NR 16 R 17 , and R 16 ; 
         each R 16 , R 17  and R 18  is independently H, C 1 -C 12  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups selected from halo, CN, —OCF 3 , CF 3 , —NO 2 , C 1 -C 6  alkyl, —OH, —SH, —O(C 1 -C 6  alkyl), —S(C 1 -C 6  alkyl), —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , —SO 2 (C 1 -C 6  alkyl), —CO 2 H, —CO 2 (C 1 -C 6  alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6  alkyl), —C(O)N(C 1 -C 6  alkyl) 2 , —N(C 1 -C 6  alkyl)C(O)(C 1 -C 6  alkyl), —NHC(O)(C 1 -C 6  alkyl), —NHSO 2 (C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)SO 2 (C 1 -C 6  alkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 6  alkyl), —SO 2 N(C 1 -C 6  alkyl) 2 , —OC(O)NH 2 , —OC(O)NH(C 1 -C 6  alkyl), —OC(O)N(C 1 -C 6  alkyl) 2 , —OC(O)O(C 1 -C 6  alkyl), —NHC(O)NH(C 1 -C 6  alkyl), —NHC(O)N(C 1 -C 6  alkyl) 2 , —N(C 1 -C 6  alkyl)C(O)NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)C(O)N(C 1 -C 6  alkyl) 2 , —NHC(O)NH(C 1 -C 6  alkyl), —NHC(O)N(C 1 -C 6  alkyl) 2 , —NHC(O)O(C 1 -C 6  alkyl), and —N(C 1 -C 6  alkyl)C(O)O(C 1 -C 6  alkyl); 
         or R 16  and R 17  together with the nitrogen to which they are attached form a 3-8 membered saturated, unsaturated or aromatic ring having 0-2 heteroatoms selected from O, S and N, wherein said ring is optionally substituted with one or more groups selected from halo, CN, —OCF 3 , CF 3 , —NO 2 , C 1 -C 6  alkyl, —OH, —SH, —O(C 1 -C 6  alkyl), —S(C 1 -C 6  alkyl), —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , —SO 2 (C 1 -C 6  alkyl), —CO 2 H, —CO 2 (C 1 -C 6  alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6  alkyl), —C(O)N(C 1 -C 6  alkyl) 2 , —N(C 1 -C 6  alkyl)C(O)(C 1 -C 6  alkyl), —NHC(O)(C 1 -C 6  alkyl), —NHSO 2 (C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)SO 2 (C 1 -C 6  alkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 6  alkyl), —SO 2 N(C 1 -C 6  alkyl) 2 , —OC(O)NH 2 , —OC(O)NH(C 1 -C 6  alkyl), —OC(O)N(C 1 -C 6  alkyl) 2 , —OC(O)O(C 1 -C 6  alkyl), —NHC(O)NH(C 1 -C 6  alkyl), —NHC(O)N(C 1 -C 6  alkyl) 2 , —N(C 1 -C 6  alkyl)C(O)NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)C(O)N(C 1 -C 6  alkyl) 2 , —NHC(O)NH(C 1 -C 6  alkyl), —NHC(O)N(C 1 -C 6  alkyl) 2 , —NHC(O)O(C 1 -C 6  alkyl), and —N(C 1 -C 6  alkyl)C(O)O(C 1 -C 6  alkyl); 
         R 19  and R 20  are independently selected from H, C 1 -C 12  alkyl, —(CH 2 ) n -aryl, —(CH 2 ) n -carbocyclyl, —(CH 2 ) n -heterocyclyl, and —(CH 2 ) n -heteroaryl; 
         each Y′ is independently O, NR 21 , or S; and 
         R 21  is H or C 1 -C 12  alkyl. 
       
     
     
       2. The compound of  claim 1  wherein R A  is H, F or Cl. 
     
     
       3. The compound of  claim 2  wherein R 1  is H, Cl, Br, F, CN, CF 3 , CHF 2 , methyl, ethyl, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, or —OCH 3 . 
     
     
       4. The compound of  claim 3  wherein R 1  is H or F. 
     
     
       5. The compound of  claim 3  wherein R 2  is H, Cl, Br, F, CN, CF 3 , CHF 2 , methyl, ethyl, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, or —OCH 3 . 
     
     
       6. The compound of  claim 5  wherein R 2  is H. 
     
     
       7. The compound of  claim 5  wherein R 3  is H, Cl, Br, F, CN, CF 3 , CHF 2 , methyl, ethyl, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, or —OCH 3 . 
     
     
       8. The compound of  claim 7  wherein R 3  is H. 
     
     
       9. The compound of  claim 7  wherein R 4  is H. 
     
     
       10. The compound of  claim 9  wherein R 5  is H or methyl. 
     
     
       11. The compound of  claim 10  wherein X 1  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
       12. The compound of  claim 10  wherein R 5  is H, R A  is H and X 1  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
       13. The compound of  claim 12  wherein X 4  is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       14. The compound of  claim 1  wherein the compound is selected from the group consisting of:
 7-(2-Fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (2-hydroxy-ethoxy)-amide; 
 7-(2-Fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid ((R)-2,3-dihydroxy-propoxy)-amide; 
 7-(2-Fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (piperidin-4-yloxy)-amide; 
 7-(2-Fluoro-4-methylsulfanyl-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid ((R)-2,3-dihydroxy-propoxy)-amide; 
 5-Chloro-7-(2-fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid ((R)-2,3-dihydroxy-propoxy)-amide; and, 
 7-(2-Fluoro-4-methylsulfanyl-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (2-hydroxy-ethoxy)-amide, or 
 
       a salt thereof. 
     
     
       15. A pharmaceutical composition comprising a compound of any one of  claims 1 - 14 , and a pharmaceutically acceptable carrier. 
     
     
       16. The pharmaceutical composition of  claim 15 , further comprising an additional chemotherapeutic agent. 
     
     
       17. The pharmaceutical composition of  claim 15 , further comprising an additional anti-inflammatory agent.